Positron emission tomography (PET) studies of cerebral receptors hold great promise in helpin, to idendfy the role of receptor defects in many diseases. To date, postsynantic receptors have been the focus of PET investigations partly because appropriate radioligands are avallable. Studies of presynaptic binding sites can provide additional insight into the pathogenesis of certain diseases which result in the selective death of brain,neurons and decreases in their axonal projections. This application proposes to develop presynaptic radioligands which bind to the serotonin re-uptake complex in the brain and, hence, will reflect the density of viable serotonin neurons in vivo for use in PET studies. The eventual long-term goal of this researc is the application of these radioligands to PET studies of disorders such as Alzheimer's and Parkinson's diseases, which have been shown to involve serotonergic deficits. It is anticipated that the radioligands developed in this work will assist in the understanding of the evolution and clinical progression of these diseases when used in concert with other radiopharmaceuticals in PET studies. Various cold (nonradioactive) chemical analogs of paroxetine, a serotonin presynaptic uptake site inhibitor, will be synthesized. The analogs will contain fluorine in a position capable of rapid radiofluorination with high specific activity 18F-fluoride (a short-lived positron emitter with a 110 min half-life). The binding characterisitics of these compounds will be evaluated in vitro to determine their potential as radioligands for PET studies. Those compounds which demonstrate a high presynaptic serotonin uptake site affinity using, in vitro competive binding, techniques will be radiolabeled with tritium. The tridum-labeled compound will be used in further studies to assess other in vitro binding parameters such as Bmax and Kd, as well as to detennine its in vivo whole body distribution, brain localization, pharmacological specificity and metabolism in rats. As a next step, those compounds displaying promising, characteristics in vitro and in rat studies will be labeled with high specific activity 18F and utilized in PET regiona localization investigations in a monkey. The presynaptic uptake site densities and dissociation binding constant for the agent will be compared to determined in the monkey. PET studies in control monkeys and serotonergic neurotoxin treated animals will be compared to determine the efficacy of the compound as a potential serotonin uptake site ligand for future PET investigadons in humans.